Metabolic stress promotes stop-codon readthrough and phenotypic heterogeneity

Significance Protein synthesis is a fundamental cellular process that occurs from bacteria to humans. Highly accurate protein synthesis has been shown to be critical for the fitness of the cell and is controlled by sophisticated molecular mechanisms. One such mechanism is the release of mature proteins at stop codons to prevent readthrough. Here we identify an environmental stress that substantially increases the level of stop-codon readthrough during protein synthesis in bacteria and provide insights into the underlying mechanism. Intriguingly, the level of readthrough fluctuates extensively among single cells that are genetically identical and grown under the same stress condition. Cells with different levels of readthrough vary in phenotypes, and individual cells with high readthrough recover better from the acid stress.